Mitochondrial Membrane Potential-dependent Endoplasmic Reticulum Fragmentation is an Important Step in Neuritic
Fei-Xiang Bao1,2, Hong-Yan Shi1,2,3, Qi Long1,2
1University of Science and Technology of China, Hefei, Anhui, China.
Background:
Neuritic degeneration is an important early pathological step in neurodegeneration.
Aim:
The purpose of this study was to explore the mechanisms connecting neuritic degeneration to the functional and morphological remodeling of endoplasmic reticulum (ER) and mitochondria.
Methods:
Here, we set up neuritic degeneration models by neurite cutting-induced neural degeneration in human-induced pluripotent stem cell-derived neurons.
Results:
We found that neuritic ER becomes fragmented and forms complexes with mitochondria, which induces IP3R-dependent mitochondrial Ca(2+) elevation and dysfunction during neuritic degeneration. Furthermore, mitochondrial membrane potential is required for ER fragmentation and mitochondrial Ca(2+) elevation during neuritic degeneration. Mechanically, tightening of the ER-mitochondria associations by expression of a short "synthetic linker" and ER Ca(2+) releasing together could promote mitochondrial Ca(2+) elevation, dysfunction, and reactive oxygen species generation.
Conclusion:
Our study reveals a dynamic remodeling of the ER-mitochondria interface underlying neuritic degeneration.
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